Genetic screening of a Dutch population with isolated GH deficiency (IGHD)

L.C.G. Graaff, J. Argente, D.C.M. Veenma, M.A.C. Herrebout, E.C.H. Friesema, A.G. Uitterlinden, M.L. Drent, A. Campos-Barros, A.C.S. Hokken-Koelega

Research output: Contribution to JournalArticleAcademicpeer-review


OBJECTIVE: Five per cent to 30% of cases of idiopathic isolated GH deficiency (IGHD) have first-degree relatives with short stature, which is suggestive of a genetic aetiology. The HYPOPIT study aimed to obtain an overall picture of gene encoding pituitary GH (GH1) and gene encoding GH releasing hormone-receptor (GHRHR) defects in a Dutch IGHD cohort and to relate them with clinical parameters.

DESIGN, PATIENTS AND MEASUREMENTS: Genetic analysis was performed of exons and exon-intron boundaries of GH1 and GHRHR in 89 Caucasian IGHD patients from 81 families, using denaturing high-performance liquid chromatography (dHPLC), DNA sequencing and multiplex ligation-dependent probe amplification. In addition, we performed functional studies on novel identified GH1 exonic variants.

RESULTS: Five different heterozygous GH1 mutations were present in 5 out of 81 participating families (6.1%), whereas no mutations in GHRHR were found. Patients with IGF-I SDS < -4.0 and peak GH levels < 5.7 mU/l had a mutation frequency of 40%, in contrast to 6.8% in patients with only one criterion, and 0.0% in patients with none of these criteria (P = 0.00007). Five new GH1 and two GHRHR variants were also identified; two of them (GH1 F92L and D153H) caused a marked reduction of GH secretion in vitro.

CONCLUSION: GH1 and GHRHR mutations are rare in Caucasian Dutch IGHD patients, which suggests the involvement of other genetic determinants in the aetiology of IGHD. IGF-I < -4.0 and peak GH levels < 5.7 mU/l are strong predictors of GH1 mutations in the studied population.

Original languageEnglish
Pages (from-to)742-750
Number of pages9
JournalClinical Endocrinology
Issue number5
Early online date31 Mar 2009
Publication statusPublished - May 2009


  • Animals
  • Body Height
  • COS Cells
  • Cercopithecus aethiops
  • Child, Preschool
  • Cohort Studies
  • European Continental Ancestry Group
  • Female
  • Gene Frequency
  • Genetic Testing
  • Genetic Variation
  • Heterozygote
  • Human Growth Hormone
  • Humans
  • Infant
  • Male
  • Mutation
  • Netherlands
  • Phenotype
  • Receptors, Neuropeptide
  • Receptors, Pituitary Hormone-Regulating Hormone
  • Recombinant Proteins
  • Transfection
  • Journal Article
  • Research Support, Non-U.S. Gov't


Dive into the research topics of 'Genetic screening of a Dutch population with isolated GH deficiency (IGHD)'. Together they form a unique fingerprint.

Cite this